Report to the European Commission

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© European Medicines Agency, 2010. Reproduction is authorised provided the source is acknowledged.

27 April 2010 EMA/50813/2009 Human Medicines Development and Evaluation

Report to the European Commission Companies and products that have benefited from any of the rewards and incentives in the paediatric regulation and the companies that have failed to comply with any of the obligations in this regulation covering the years 2007 to 2009

Prepared by the Section Paediatric Medicines Human Medicines Special Areas Sector European Medicines Agency

Report to the European Commission EMA/50813/2009 Page 2/34

Table of contents

1. INTRODUCTION..................................................................................... 4 1.1. Scope of the report...............................................................................................4 1.2. Data collection .....................................................................................................4 1.3. Overview of the implementation of the Paediatric Regulation .....................................5

2. COMPANIES AND PRODUCTS THAT HAVE BENEFITED FROM ANY OF THE REWARDS AND INCENTIVES IN THE REGULATION ...................................... 6 2.1. Scientific advice ...................................................................................................6 2.1.1. Advice from the Agency......................................................................................6 2.1.2. Advice from the National Competent Authorities ....................................................7 2.2. Paediatric Investigation Plans – Waiver ...................................................................7 2.3. Compliance statement included in a marketing authorisation .....................................9 2.3.1. Compliance statement for centrally-authorised medicinal products...........................9 2.3.2. Compliance statement for medicinal products authorised through national/decentralised/mutual recognition procedure, including those subject to Article 29 of the Paediatric Regulation .............................................................................................9 2.4. Extension of the Supplementary Protection Certificate/Market Exclusivity ..................10 2.5. Marketing authorisation granted or varied with mention of the waiver or deferral in the Summary of Product Characteristics ............................................................................10 2.6. Price/reimbursement benefits ..............................................................................12 2.7. Research incentives ............................................................................................12 2.7.1. EU Framework Programme ...............................................................................12 2.7.2. European Network of Paediatric Research at the European Medicines Agency ..........12 2.7.3. National initiatives ...........................................................................................13 2.8. Authorisation of paediatric clinical trials.................................................................15 2.9. Procedures for marketing authorisation .................................................................15 2.10. Article 45/46 of the Paediatric Regulation ............................................................17 2.10.1. Article 45......................................................................................................17 2.10.2. Article 46......................................................................................................17

3. FAILURE TO COMPLY WITH THE OBLIGATIONS SET IN THE PAEDIATRIC REGULATION ............................................................................................. 19 3.1. Submissions of the PIP/waiver application to the PDCO ...........................................19 3.2. Validation of application for marketing authorisation/extension ................................19 3.3. Compliance with the paediatric requirements and rewards.......................................20 3.4. Mention of the Decision on waivers or deferrals in the product information ................20 3.5. Annual reports on deferrals .................................................................................20


4. CONCLUSION......................................................................................... 20

Annex 1 - Questions sent to the Member States ........................................ 22

Annex 2 - Compliance statement included in a marketing authorisation for products authorised through national/decentralised/mutual recognition procedure.................................................................................................. 24

Annex 3 - 6-months extension of the supplementary protection certificate (SPC) granted by the National Patent Office ............................................. 28

Annex 4 – List of projects on off-patent medicines funded by the European Commission through the EU Framework Programme................................. 31

Annex 5 - List of products and resulting amendment of the SmPC further to submission of data through article 45 and 46............................................ 32


1. INTRODUCTION

1.1. Scope of the report

Regulation (EC) No. 1901/2006 of the European Parliament and of the Council on medicinal products

for paediatric use and amending Regulation (EEC) No 1768/92, Directive 2001/20/EC, Directive

2001/83/EC and Regulation (EC) No 726/2004 (hereinafter 'the Paediatric Regulation') was adopted on

12th December 2006. It was published in the Official Journal of the European Communities on 27th

December 2006 and entered into force on 27th January 2007.

Article 50(1) states: “On the basis of a report from the Agency, and at least on an annual basis, the

Commission shall make public a list of the companies and of the products that have benefited from any

of the rewards and incentives in this Regulation and the companies that have failed to comply with any

of the obligations in this Regulation. The Member States shall provide this information to the Agency.”

Considering the early days of the implementation of the Paediatric Regulation and the lack of internal

resources, the European Medicines Agency (hereafter “the Agency”) was not able to produce such a

report for the years 2007 and 2008. This report therefore covers the whole period from the entry into

force of the Paediatric Regulation, i.e. 26 January 2007 to 31 December 2009.

As explicitly requested, this report lists the companies and products that have benefited from any of

the rewards and incentives defined in this Regulation both at the European Union and at national level.

The report examines also the situation where companies would have failed to comply with any of the

obligations set in this Regulation. The figures reported correspond to procedures with the start date

within the year.

Incentives available at EU level are supported by complementary national initiatives, particularly in

areas such as fiscal incentives and national research projects. Pursuant to Article 39(2) of the

Paediatric Regulation, the European Commission published such inventory on national measures based

on information received from 18 of 27 Member States on 30 July 2008.

1.2. Data collection

The Agency sent a letter on 10 December 2009 to all Member States to require contributions to

prepare this report (Letter sent to Permanent Representatives of the Member States of the European

Union with a response requested by 31 January 2010). The letter contained a list of information to be

provided (Annex 1).

We also contacted the DG Research to obtain information on the projects funded through the

framework programme in the context of the Paediatric Regulation.

The Agency also sent a copy of this letter to the Heads of Agencies and informed the Coordination

Group for Mutual Recognition and Decentralised Procedure – human, accordingly. In order to obtain

the highest return rate, a reminder was sent on 11 February 2010.

The Agency received feedback from 22 Member States:

Austria- Belgium - Bulgaria – Czech Republic - Cyprus – Denmark - Estonia – France - Finland –

Germany – Hungary - Ireland – Italy – Latvia – Lithuania – Luxembourg – Malta - The Netherlands -

Romania - Slovak Republic - Slovenia – Sweden - United Kingdom.

No answer has been received from Greece – Poland - Portugal – Spain.

Information was also received from EFTA States. The Paediatric Regulation is not yet part of the EEA

Agreement and therefore is not yet implemented in EFTA States (Iceland, Liechtenstein and Norway).


Nonetheless Iceland and Norway have actively contributed to the work of the Paediatric Committee

since the beginning. In addition they requested the submission of paediatric data according to Article

45 and 46 of the Paediatric Regulation and are participating in the worksharing for assessment of these

data.

This report is not comprehensive. The limit of the methodology used is that some data was not

provided by all Member States. For instance some of the requested information may only be available

from certain bodies of the Member States such as the National Patent Office, the Competent Authority

for Medicinal Products, or the Ministry of Health. Therefore depending on the process chosen by the

Member State to collect such data, the feedback received varied substantially.

Some Member States provided additional information on some measures taken at national level. These

have been annexed to this report for completeness.

According to the Paediatric Regulation, the Agency should produce such report annually. Based on this

year’s experience, the Agency will reflect on how to improve the method to help Member States

collecting the data.

1.3. Overview of the implementation of the Paediatric Regulation

Three years have elapsed since the entry into force of the Paediatric Regulation whose objectives are:

i) to increase the availability of medicines intended for children, ii) to make information on those

medicines widely available and iii) to stimulate high quality paediatric research. This Regulation

includes a set of obligations and rewards/incentives for industry to compensate the investment in

paediatric development.

One of the pillars of the Regulation is the Paediatric Committee (PDCO) which is primarily responsible

for reviewing and agreeing applications for paediatric investigation plans (PIPs) including deferrals,

and/or waivers. Since its first meeting on 4 July 2007, the PDCO has performed strongly as shown by

the figures presented later in the report. This has been possible thanks to the preparation and

motivation of Committee members, supported for most of them by the National Competent Authorities,

as all of them have actively participated in the review process, as well as to the Agency secretariat,

namely the Paediatric Medicines section of the Human Special Areas sector, which supports the

Committee in its activities.

The Paediatric Regulation has created a series of new tasks for the Agency and for the Member States

which had an impact on the resources at Agency as well as at the National Competent Authorities level.

Most of the tasks have been dealt with, and the legal deadlines have been met with success. Again this

has been possible thanks to the cooperation of all partners and stakeholders, in particular learned

societies and industry.

Further information on the status of the implementation of the Paediatric Regulation with respect to

the various topics covered can be found on the Agency website (Medicines for Children

http://www.ema.europa.eu/htms/human/paediatrics/introduction.htm).


2. COMPANIES AND PRODUCTS THAT HAVE BENEFITED FROM ANY OF THE REWARDS AND INCENTIVES IN THE REGULATION

2.1. Scientific advice

2.1.1. Advice from the Agency

In accordance with Article 26 of the Regulation, the Agency provides free scientific advice for any

paediatric questions. Scientific advice and protocol assistance (the special form of scientific advice

available for the development of designated medicines for 'orphan' or rare diseases) may be given to

companies on the design and conduct of trials necessary to demonstrate the quality, safety and

efficacy of the medicinal product in the paediatric population. The advice is provided by the Scientific

Advice Working Party of the Committee for Medicinal Products for Human Use (CHMP) and is adopted

by the CHMP. For the paediatric ones, members of the PDCO are routinely involved in the procedure as

experts. This is part of the collaboration established under the Executive Director’s responsibility

(article 3(3) of the Paediatric Regulation).

Applicants may choose to request scientific advice before submitting an application for a PIP to help

them to prepare such plan, or after the Agency Decision to discuss, for example, combined adult and

paediatric development in light of the PIP requirements. Some companies have submitted

simultaneous applications for a PIP and request for a scientific advice, but this is discouraged as the

procedures overlap creating unnecessary duplication of work. In addition despite active collaboration

between the PDCO and the Scientific Advice Working Party, a risk of divergence cannot be ruled out as

the two groups may not have the possibility to discuss all details of the applications.

At the difference of the decision on a PIP, scientific advice/protocol assistance received from the

Agency is not binding, either on the Agency, CHMP or on the sponsor, with regard to any future

marketing-authorisation application for the product concerned.

Since the entry into force of the Paediatric Regulation the number of such requests has increased

steadily (table 1).

Table 1. Number of requests for paediatric scientific advice(SA)/protocol assistance (PA) and follow-ups

Year 2007 Year 2008 Year 2009

Total SA requests 213 264 311

Total PA requests 68 56 77

Paediatric scientific advice 14 13 14

Paediatric follow-up SA 4 5 9

Paediatric protocol assistance - 5 4

Paediatric follow-up PA 3 - 3

Total paediatric SA+PA 21 23 30

As the information on scientific advice is considered commercially confidential, the list of the

companies and products which have benefited from this incentive is not included in this report but can

be found as a separate document.

A high number of mixed scientific advice/protocol assistance requests for adult and paediatric

development have also been submitted for which members of the PDCO may also be involved (see


table 2). As these mixed scientific advices are not free of charge and as protocol assistance is funded

by the EU’s special contribution, this is not part of the incentives provided by the Regulation and

therefore the corresponding list of companies and products that have applied for such mixed requests

is not reported.

Table 2. Number of mixed requests for scientific advice/protocol assistance and follow-up (i.e. including questions on the paediatric development)

Year 2007 Year 2008 Year 2009

scientific advices Not reported 6 16

follow-up scientific

advice

id 1 8

protocol assistance id 1 8

follow-up protocol

assistance

id 1 3

2.1.2. Advice from the National Competent Authorities

Some Member States also provided national scientific advice to help paediatric development.

Based on the information received from the Member States, there is no fee reduction for scientific

advice for the development of medicines for paediatric use in Malta, Latvia, Finland, Germany,

Hungary, Slovenia, Cyprus, Austria, Italy and Bulgaria.

In Belgium, 6 requests for national scientific advice were addressed to the agency which contained at

least 1 question on paediatric development. As none were dealing with paediatric development only, no

fee reductions were attributed.

In Finland the National Agency for Medicine gave one scientific advice including paediatrics to a

company for a product in August 2008.

In Sweden, in 2007, the agency (MPA) provided 172 advices of which 22 were relevant to paediatric

development. In 2008, the proportion was 13 out of 221 and in 2009, 16 out of 198 scientific advice.

As the information on scientific advice is considered commercially confidential, the list of the

companies and products who have received scientific advice is not included in this report but can be

found as a separate document.

In the United Kingdom, a fee waiver is offered for products undergoing paediatric development. One

such meeting was held in 2009. Details of products in scientific advice meetings are not placed in the

public domain. Advice concerning paediatric development of other products has been given in the

period 2007-2009 by the UK, but these requests were mixed requests, so the fee waiver has not

applied these cases.

No specific information has been received from Czech Republic – Denmark - Estonia – France - Ireland-

– Lithuania - Luxembourg – The Netherlands – Romania - Slovak Republic.

2.2. Paediatric Investigation Plans – Waiver

Applications

From August 2007 to December 2009, the PDCO received 629 validated applications of which 156

(25%) were requests for a full waiver for all conditions and all subsets of the paediatric population.


Of the 629 validated applications which covered 961 indications (on average 1.5 indications per

product):

• 416 applications (66%) referred to medicinal products not yet authorised in the EU at the time of

the entry into force of the Regulation (so called “Article 7 applications”).

• 192 applications (31%) referred to products already authorised, still under patent or

supplementary Protection certificate, in view of a submission of a variation/extension for a new

indication, pharmaceutical form or route of administration (so called “Article 8 applications”).

• 21 Applications (3%) referred to an off-patent product developed specifically for children with an

age-appropriate formulation (so called “Article 30 applications” with a view to submit a Paediatric

Use Marketing authorisation or PUMA).

In the infancy of the implementation of the Regulation, most of the applications were “Article 8

applications”. After about a year, the balance changed with a higher proportion of “Article 7

applications”.

Opinions

As a result of the assessment of these applications, the PDCO has since its first meeting in July 2007

adopted:

• 125 positive opinions on product-specific waivers (36%).

• 205 positive opinions on a PIP (59%). An opinion on a PIP may also contain a deferral and/or

waiver of the obligation to gather clinical trial data in certain age groups of children.

• 17 negative opinions (5%).

Since 2008 which saw the first Decision, the details of the decisions issued by the Agency on the PDCO

opinions are published in a summarised form and can be found on the following webpage:

http://www.ema.europa.eu/htms/human/paediatrics/decisions.htm.

Class Waivers

To effectively manage the anticipated high level of applications and in accordance with the Regulation,

very early on, the PDCO adopted a list of conditions that occur only in adult populations for which all

classes of medicinal products intended to treat these conditions would be exempt from the requirement

for a PIP and/or from the submission of an application for a product-specific waiver. The list is updated

at least once a year. In addition, the PDCO has adopted an opinion on a class of products (in a

condition) for which, similarly, there is an exemption.

The Agency decisions on the PDCO opinions on the class waivers can be found on the following

webpage: http://www.ema.europa.eu/htms/human/paediatrics/decisions.htm.

Modifications of agreed PIPs

Although it is too early for a prediction, it is anticipated that the number of requests for modifications

of an agreed PIP will increase exponentially over the coming years. Indeed in order to establish an

early dialogue between the sponsor and the PDCO, the Regulation sets a deadline for the submission of

the application for a PIP and/or waiver at the early stage of the development of the medicinal product.

As the development of medicinal products is a dynamic process depending on the results of ongoing

studies, it is estimated that 3 to 5 modifications will be submitted per agreed PIPs. As of December

2009, the PDCO already adopted 59 positive opinions on modifications of an agreed PIP.


2.3. Compliance statement included in a marketing authorisation

Once the PIP is completed, there is a need to check compliance, i.e. to verify that the measures set out

in the Agency decision have been carried out in accordance with the agreed PIP, including its timelines.

This is done at the time of validation either of applications for marketing authorisation, or of

variation/extensions, or prior to the submission of the application, on request from the applicant to the

PDCO.

Until now and as a pilot phase, the National Competent Authorities have requested the PDCO to check

the compliance check on their behalf.

Opinions of the PDCO on compliance are provided once the PIP is completed. As of December 2009,

the number of PDCO positive opinions on compliance with an agreed PIP reached 13. The PDCO also

adopted 1 negative opinion on compliance.

2.3.1. Compliance statement for centrally-authorised medicinal products

For 3 centrally authorised medicinal products, 2 companies have already provided the results of all

studies performed in compliance with an agreed PIP as part of the submission of an application for

authorisation of new indications, including paediatric indications, new pharmaceutical forms and new

routes of administration. This has resulted in a compliance statement included in the marketing

authorisation by the European Commission (Table 3).

Table 3. List of companies and products with a compliance statement (centrally approved)

Companies Products: invented name (international non-proprietary name)

Year

2008

Merck Sharp

and Dohme

Cancidas (caspofungin)

http://www.ema.europa.eu/humandocs/Humans/EPAR/cancidas/cancidasM2.ht

m

Year

2009

Schering-

Plough

Europe

Schering-

Plough

Europe

Rebetol (ribavirin)

http://www.ema.europa.eu/humandocs/Humans/EPAR/rebetol/rebetolM2.htm

PegIntron/Viraferon peg (peginterferon alfa-2b)

http://www.ema.europa.eu/humandocs/Humans/EPAR/pegintron/pegintronM2.h

tm

http://www.ema.europa.eu/humandocs/Humans/EPAR/viraferonpeg/viraferonpe

gM2.htm

2.3.2. Compliance statement for medicinal products authorised through national/decentralised/mutual recognition procedure, including those subject to Article 29 of the Paediatric Regulation

The list of companies and products which have benefited from the inclusion of the compliance

statement is presented in Annex 2. So far this list includes only the products which have been subject

to an “Article 29” procedure of the Paediatric Regulation. This procedure allows companies to submit

an application to the Agency for a new indication (including in children), pharmaceutical form or route

of administration for medicines that are already authorised at the level of the Member States. Data

supporting such applications have to be generated in accordance with an agreed paediatric

investigation plan (PIP). This results in the adoption of an EU harmonised decision on the use of a

medicinal product in the paediatric population. Once the Commission Decision is adopted, the Member

States are required to vary the terms of an existing marketing authorisation as necessary, to comply

with the Decision within 30 days of its notification.


Table 4. Commission Decisions for medicinal products for human use, pursuant to Article 29 of Regulation (EC) No 1901/2006, with a compliance statement

Companies Products: invented name (international non-proprietary name)

Year

2008

Merck Sharp

and Dohme BV

Cozaar and associated names (losartan)

Commission Decision C(2009)488

http://www.ema.europa.eu/pdfs/human/press/pr/55020608en.pdf

Year

2009

AstraZeneca

AB

Novartis

Pharma AG

Arimidex and associated names (anastrazole) Commission Decision

C(2009)8750


Diovan and associated names (valsartan) –(CHMP Opinion adopted in

December 2009)


2.4. Extension of the Supplementary Protection Certificate/Market Exclusivity

In order to be eligible for an extension of the Supplementary Protection Certificate (SPC) by 6 months,

several conditions need to be met (assuming that the SPC extension application is made in due time

and complies with the provisions of Regulation (EC) No 469/2009):

i) he compliance statement with the agreed PIP is included in the marketing authorisation;

ii) there is an authorisation of the medicinal product in all Member States;

iii) there is an update of the Summary of Product Characteristics (SmPC) with results of the studies

conducted in compliance with the agreed PIP. This applies even if the results fail to lead to the

authorisation of a paediatric indication.

• Extensions of the supplementary protection certificate are granted by the National Patent Offices at

national level. Therefore the companies will have to file for an SPC extension with the NPO of each

and every Member State where the active substance used for the medicinal product is protected by

a basic patent or an SPC.

Annex 3 compiles the information received from Member States on those products which have

fulfilled the paediatric requirements and therefore have been granted by the National Patent Offices

a 6-month extension of the Supplementary Protection Certificate.

• For orphan medicinal products, the reward is a 2-year extension of the market exclusivity. So far

no orphan medicinal product has benefited from this reward. Orphan medicines represent

approximately 20% of the applications for PIPs and waivers.

As no PUMA has yet been authorised, no company has benefited from the defined data and

marketing protections periods.

2.5. Marketing authorisation granted or varied with mention of the waiver or deferral in the Summary of Product Characteristics

According to Article 28(2) of the Paediatric Regulation, any Agency decision on a waiver or deferral is

recorded in the Summary of Product Characteristics (SmPC) and if appropriate in the package leaflet of

the product concerned when the initial marketing authorisation is granted or when the marketing

authorisation is varied to include a new indication, including paediatric indication, new pharmaceutical

form or new route of administration.


As of December 2009, 10 centrally authorised medicinal products had such a statement (table 5). The

results of the studies performed in compliance with an agreed PIP, even those which failed to lead to

an indication, are also to be reflected in the SmPC.

Table 5. List of products and companies for which a statement has been included in SmPC

Invented

name

International

non-proprietary

name

Marketing

authorisation

holder

Statement

on waiver

Statement

on

deferral

Date of

marketing

authorisation

/variation

Menveo

MenACWY Novartis Vaccines

and Diagnostics SRL

√ √ CHMP Opinion

Dec 2009 (EC

decision

pending)

Orencia

Abatacept Bristol Myers Squibb

Pharma EEIG

√ January 2010

Urorec/

Silodex

Silodosin Recordati Ireland ltd √ CHMP Opinion

Nov 2009 (EC

decision

awaited)

Onbrez/

Oslif

/Hirobriz/

Breezhalers

Indacaterol

maleate

Novartis Europharm

Ltd

√

30 Nov 2009

Exforge

HCT

Imprida

HCT

Dafiro HCT

Copalia HCT

Amlodipine

besylate/

valsartan/

hydrochloro-

thiazide

Novartis Europharm

Ltd

√ 16 Oct 2009

Duocover Clopidrogel/acetyl

salicylic acid

Bristol-Myers Squibb

Pharma EEIG

√ CHMP Opinion

Dec 2009 (EC

decision

pending)

Duoplavin Clopidrogel/acetyl

salicylic acid

Sanofi Pharma

Bristol-Myers Squibb

SNC

√ CHMP Opinion

Dec 2009 (EC

decision

pending)

Elonva Corifollitropin N. V. Organon √ CHMP Opinion

Nov 2009 (EC

decision 25

January 2010)

See also section 2.4.

So far based on the information received it seems that none of the medicinal products authorised

through national/decentralised/mutual recognition procedure, have such a statement included in their

SmPC.


2.6. Price/reimbursement benefits

On the basis of the information provided by some Member States, it appears that none of those having

answered had introduced any concession for medicinal products for paediatric use in connection with

the fixing of prices and reimbursement. Similarly, it seems that no specific measures have been

introduced to favour a priority review for determining the price and reimbursement for medicinal

products for paediatric use.

The feedback received from Lithuania specifically indicates that no special price/reimbursement

benefits for paediatric medicinal products are foreseen in the legislation. However special conditions for

reimbursement of medicinal products intended for treatment of children exist. That means that all

medicinal products included into positive lists, (i.e. the list of diseases and the reimbursed medicinal

products used for their treatment and the list of reimbursed medicinal products) may be prescribed for

children until 18 years by applying 100% compensation of a basic price.

The United Kingdom explained that, under the Pharmaceutical Price Regulation Scheme (PPRS),

companies may benefit from the variable rate for paediatrics element of the R&D allowance. However,

the amount is small (a maximum of 3% of a company's sales of branded medicines to the NHS) and in

practice only one or two companies have claimed the paediatrics element. Companies have not

benefited materially as the amount was insufficient to generate a price increase for the company or to

reduce the amount of excess profits repayable under the PPRS and so NHS list prices were unchanged.

2.7. Research incentives

2.7.1. EU Framework Programme

Thanks to the Paediatric Regulation (Article 40), funding of studies into off-patent medicinal products

(i.e. those not covered by a patent or supplementary protection certificate) is available. This funding,

provided through the EU Framework Programmes for Research and Technological Development, covers

the development of off-patent medicinal products with a view to the submission of an application for a

PUMA. In order to ensure that funds are directed into research of medicinal products with the highest

need in the paediatric population and in agreement with DG Research, the PDCO has adopted a priority

list of off-patent products for which studies are required in advance of each call.

The European Commission has already launched four calls within the 7th Framework Programme. Six

projects have been funded in response to the second (first paediatric) call in 2007 with a budget of

about €22 million for 3 years (maximum of €6 million per project), and three projects have been

funded in response to the third call with a budget of about €18 million. The procedure for selecting the

projects in response to the fourth call is ongoing. This year the PDCO will adopt a new revised list in

advance of the next call. The fourth call with a total budget available of 40 million Euros was issued in

September 2009. The selection process is ongoing and three projects have been proposed to be

funded. For this call, the Commission, with the involvement of the Agency has initiated a greater

collaboration with the US (FDA/NIH) in order to have a close co-operation for research in paediatrics

and thereby avoiding any unnecessary duplication of studies. Further details of these projects can be

found in Annex 4 as provided by DG Research.

2.7.2. European Network of Paediatric Research at the European Medicines Agency

The Paediatric Regulation requires the setting up of a European network of existing national and

European networks, investigators and centers with specific expertise in the performance of studies in

the paediatric population coordinated by the Agency. Further to the adoption of the implementing


strategy for the network by the Agency Management Board on 15 January 2008 the network has been

set up. Although the network will not fund studies or research per se, its objectives are to coordinate

studies relating to paediatric medicinal products, to build up the necessary scientific and administrative

competences at European level, in order to avoid duplication of studies and testing in children.

Companies will therefore benefit for having such a network as a tool for the development of medicinal

products in children. Up to 60 networks have been identified and work is ongoing to implement the

recognition criteria and the Coordinating Group.

2.7.3. National initiatives

Some initiatives have been taken for funding the development of medicinal products for paediatric use

at national level. The following feedback from the following Member States has been received.

Belgium

The Belgian agency launched the Belgian Paediatric Research Network in collaboration with the Belgian

Paediatric Association.

Germany

There is a survey on off-label use “Off-Label-Use von Arzneimitteln bei Kindern und Jugendlichen in

Deutschland – Ergebnisse von KiGGS (Kinder-und Jugendgesundheitssurvey)” (Off-label use of

medicinal products in children and adolescents in Germany - Results from the KiGGS (Children and

Adolescent Health Survey), Budget Euros 28,520.00.

Hungary

There are some measures of general scope which may promote the research and development of

paediatric medicines.

In July 2009, an Action Plan for the Pharmaceutical Industry and Biotechnology was adopted which

provides for the deduction of R&D costs from certain payment obligations on the pharmaceutical

companies. Currently the deduction rate is 20% of the R&D investment, but from 2011 the total

amount invested shall be taken into account. Although so far this incentive has not been explicitly used

for paediatrics medicines R&D, it is hoped that pharmaceutical companies will extend their innovation

activities to this direction as well.

Italy

Independent research is funded by AIFA. The promotion of independent research on drugs represents

one of the strategic tasks assigned to AIFA by Italian Legislation. The general aim of the program is to

support clinical research on drugs in areas of interest for the National Health Service (NHS) and where

commercial support is normally insufficient. The target populations are patients normally excluded by

clinical studies on efficacy and safety, such as children, pregnant women and the elderly. The focusing

research issues are those less explored in commercial research, such as clinically relevant end points,

relative efficacy of drugs (including the assessment of multimodal strategies) and long term follow up

on efficacy and safety of therapies.

AIFA set up the program on independent research in 2005, and five calls for proposals (2005 2006-

2006-2007-2008-2009) have already been launched. The call for proposals is aimed at investigators

working in public (e.g. national health service [SSN], universities, etc.) or non-profit organisations

(e.g. scientific foundations, patient associations, etc.).


The way of funding this independent research derives from an ad hoc fund set up, requiring

pharmaceutical companies to contribute 5% of their yearly expenditure devoted to promotional

initiatives.

Regarding the period of interest of this Report, years 2007-2009, AIFA has selected several protocols

to be funded (program 2007 and program 2008). Program 2009 has just been launched and the

preliminary results will be available in April 2010.

See separate document (Additional information provided by Member States) ‘Paediatric Studies funded

by AIFA 2007-2008’ for the paediatric protocols funded in 2007 and 2008.

Framework agreements

The Italian Medicines Agency, through the Framework Agreements on Research & Development,

promotes at national level investment in production, research and development in the pharmaceutical

sector, according to the ten-year European Union Programme of renewal and encouragement of the

economic and social environment, as defined by the Lisbon European Council. Framework Agreements

are intended for pharmaceutical companies operating in the Italian territory, which are selected for

admission to the funding through a specific call for proposals that AIFA launched in 2008. Investment,

amounting to a total of €100 million, is destined to:

• The promotion of phase I and II clinical trials in Italy.

• The establishment or expansion of production sites (including feasibility studies, land, buildings,

machinery).

• The opening or improvement of research laboratories.

• The hiring of new permanent staff involved in production.

• The hiring of new permanent staff assigned to R&D activities.

In 2008 52 companies submitted proposals for 114 projects. An appointed Commission assessed the

most interesting projects to be funded: 29 projects are focusing on pre-clinical research; 15 on clinical

trials and 15 on production sites. Projects involving paediatrics are listed in the document “Framework

Agreements by AIFA in 2008 (Projects in Paediatric Field)” (Additional information provided by Member

States).

The Netherlands

There is a grant for development via ZonMw: the Netherlands organisation for health research and

development. The Ministry of Health has given ZonMw the assignment to start a programme on the

promotion of pharmaceuticals for children. The programme started in 2009 and lasts till 2017 with a

budget of 14.3 million Euros.

The Medicines for Children Research Network (MCRN) is a network of Dutch paediatricians of university

paediatric hospitals. The MCRN receives its money from a starting grant (2008-2011) of the

Netherlands Federation of University Medical Centres (NFU), Nefarma and the Ministry of Health. The

MCRN needs to generate its own income from 2012 onwards and be financially independent.

Lithuania

There are possibilities to get financial support available through available financial programmes

coordinated by the Ministry of Economy. So far, domestic companies involved in research and

development of medicinal product did not submit any applications to take part in tendering processes.


Malta

Research on medicinal products inclusive for paediatric use can be funded under the National Research

and Innovation Programme set up by the Malta Council for Science and Technology. However there is

no specific incentive in place for developing paediatric medicines.

United Kingdom

The UK Government provides support for the Medicines for Children Research Network which provides

infrastructure to encourage and support paediatric studies although not direct funding. The work of this

Network is described in a separate document (Additional information provided by Member States).

Grants for particular products intended for use in children may have been awarded under a number

of other general research programmes, but this information is not readily available. In addition to the

research network, the UK NHS provides experts who advise the UK Licensing Authority on the quality,

safety and efficacy of paediatric medicines in the context of the Paediatric Regulation, through the

Paediatric Medicines Expert Advisory Group of the Commission on Human Medicines. This work is not

directly remunerated and is therefore supported by the UK Government.

2.8. Authorisation of paediatric clinical trials

The European Medicines Agency has no responsibility in the authorisation of clinical trials in the EU.

This is under the responsibility of the Member States according to Directive 2001/20/EC.

For those Member States who have answered the question, no fee reduction/fee waiver or priority

review has been introduced with respect to paediatric products.

Collaboration of the PDCO with the Clinical Trials Facilitation Group (CTFG) has been initiated to resolve

potential issues of divergences between PDCO and national competent authorities regarding the trials

from the PIP that the Competent Authorities are supervising. The CTFG will have direct access to the

paediatric database and PIP evaluation, thereby allowing immediate retrieval of information regarding

the clinical trials included in the PIP opinions.

The Slovak Republic and Sweden took the initiative to send a list of paediatric trials that have been

authorised by them. This list is not included in this report but can be found as a separate document.

It has to be kept in mind that one of the provisions of the Paediatric Regulation is to make public the

information on paediatric trials entered into the EU Database on Clinical Trials (EudraCT). The Agency

with its PDCO have been working with the European Commission to produce guidance on the protocol-

related information and on the results concerning paediatric clinical trials to be entered as well as the

information to be made public. This year will see the first roll-out of publicly available protocol-related

information. Results-related information will follow.

2.9. Procedures for marketing authorisation

The existing procedures for the granting of a marketing authorisation of medicinal products and for

extension of the marketing authorisation to add a new indication, pharmaceutical form and/or route of

administration have not been changed.

The Paediatric Regulation has however introduced a new type of marketing authorisation: the

paediatric-use marketing authorisation (PUMA); it may be requested for a medicine which is already

authorised or not, but in all cases no longer covered by intellectual property rights (patent,

supplementary protection certificate), and which will be exclusively developed for use in children in

compliance with an agreed PIP. This type of marketing authorisation will cover the indication(s) and


age-appropriate formulation for the paediatric population. A paediatric-use marketing authorisation will

benefit from 10 years of market protection as an incentive to the development in children. The

submission of an application for a PUMA is automatically eligible to the centralised procedure but it

may also be made through the national/decentralised/mutual recognition procedures.

At the European Medicines Agency level there are no specific provisions to either prioritise or

accelerate the review of medicinal products intended for use in children, including for PUMA. However

the CHMP may consider shortening the review time for such products, in accordance with the

accelerated assessment procedure.

With respect to the fees, the European Medicines Agency has decided not to introduce any fee

reduction for centralised procedure for medicinal products indicated in children or for extension of the

marketing authorisation to add a new paediatric indication, pharmaceutical form and/or route of

administration relevant for paediatric use. However, with respect to PUMA and in line with Article 47 of

the Regulation, the Agency is granting a partial exemption from the payment of the fees laid down in

the fee regulation for paediatric use marketing authorisation applications submitted under Article 30 of

Regulation (EC) No 1901/2006 on medicinal products for paediatric use. So far there has been no

application for PUMA and therefore no companies have benefited from this.

At national level some initiatives have also been taken. The following feedback from Member States

has been received.

Belgium

A policy for priority review of the applications for variations was introduced, but it has not been used

because no case occurred where it could have been applied.

Hungary

The National Institute of Pharmacy is considering giving priority to paediatrics related dossiers in the

near future. These measures may include either more rapid processing of applications for marketing

authorisations or provision of scientific advice.

Slovak Republic

Fees for authorisation of medicines in the Slovak Republic are far below average EU fees. Therefore in

2008 the Slovak agency has proposed a new fee scheme in this respect which is still in progress in the

Ministry of Health. This proposed new scheme for fees would allow introducing differences in fees in

this respect.

United Kingdom

A fee waiver applies in certain cases for products being developed specifically for paediatric use, for

example a new paediatric formulation or extension of indications into the paediatric population. One

such application (which has not needed to comply with a PIP) has been received but is pending

approval.

The United Kingdom has a system of priority reviews which would include paediatric medicines but is

not specific to that category. UK has approved one such request but an application has not yet been

submitted.

For the other Member States, either no such initiatives have been taken or no information was

received.


2.10. Article 45/46 of the Paediatric Regulation

2.10.1. Article 45

In accordance with Article 45 of the Paediatric Regulation, marketing authorisation holders were

required to submit to the competent authorities all paediatric studies completed by the date of entry

into force of the Regulation. These studies were to be submitted by 26 January 2008. Upon

assessment of these data the competent authority may update the SmPC and package leaflet and may

vary the marketing authorisation.

• For centrally authorised medicinal products, data have been submitted for approximately 60

products. The assessment of the data resulted to an update of the SmPC for only 4 medicinal

products. For these 4 cases there was no update of the package leaflet was amended. There are

still a couple of procedures ongoing.

The figures may be underestimated as in order to streamline the process, when regulatory action

was deemed necessary (i.e. where amendments to SmPC, labelling and/or PL were identified by

the MAH) MAHs were advised to straightaway submit a variation containing the Article 45

paediatric studies.

• For products authorised through national/decentralised/mutual recognition procedure the extent of

information received has been enormous. Information has been received for approximately 1000

active substances, with several documents for each of them (some may relate to the same study).

To cope with the workload, there is an ongoing work-sharing exercise between the Member States

and the assessment is being performed in stages. Four waves have been agreed, and the

assessment has already been completed for 11 medicines, for which Paediatric Assessment reports

have been published on the Head of Agencies website.

Both at the level of CHMP and of the Member States it was considered that the data assessed

were, in most cases, either of insufficient quality and too limited to lead to a change in the SmPC

of the information related to the use in children.

2.10.2. Article 46

In accordance with Article 46 of the Paediatric Regulation the MAH has the obligation to submit to the

Competent Authority any MAH-sponsored studies involving the use in the paediatric population of an

authorised medicinal product, whether or not they are part of a PIP, within 6 months of completion.

• For centrally authorised products, studies have so far been submitted for about 24 products, and

this has led to an update of the SmPC in only 2 occasions. The CHMP has been reminded of the

importance of systematically including information into the SmPC. As for Article 45, the figures are

approximate as similarly, when regulatory action is necessary (i.e. in case amendments to SmPC,

labelling and/or PL are identified by the MAH) MAHs are advised to straightaway submit a variation

containing the Article 46 paediatric study(ies). In some cases it was agreed that the assessment of

the data would be postponed as the MAHs intended to submit a variation procedure within a short

period of time. It is therefore difficult to conclude on how many cases the submission of these data

has truly led to a change of the Summary of Products Characteristics.

• For nationally authorised medicinal products and those authorised through mutual recognition, or

decentralised procedures, studies have been received for 70 medicinal products.

While Article 45 was a retrospective exercise and therefore the data were submitted at about the same

time, the obligation set by Article 46 is prospective. As such the number of studies to be submitted is

anticipated to increase steadily over the years.


The list of products and resulting amendments of the SmPCs further to submission of data through

Article 45 and 46 are presented in Annex 5.


3. FAILURE TO COMPLY WITH THE OBLIGATIONS SET IN THE PAEDIATRIC REGULATION

3.1. Submissions of the PIP/waiver application to the PDCO

Article 16 of the Paediatric Regulation requires companies to submit applications for a PIP or a waiver

for agreement no later than upon completion of the human pharmacokinetic studies in adults except

where duly justified. It was agreed that this corresponds approximately to the end of phase 1.

In the early days of the entry into force of the Regulation, the companies submitted their application as

soon as it was possible, but for the majority the overall development of the product was already

beyond that stage and often reaching confirmatory (phase III) clinical trials in adults, to comply with

the new requirements for products already in development.

However, it is clear that late submissions of PIP/Waivers applications have occurred in a number of

cases, causing a delay in the submission or the validation of the application for the marketing

authorisation in adults, as the applicant did not have an Agency Decision on a PIP including a deferral

and/or on a waiver. This also forced the PDCO to evaluate PIP applications with proposed trials and

studies that were already ongoing or completed; in many cases the proposal of the applicant was not

considered satisfactory but could not be modified. The PDCO considered at the same time that

requesting new studies would have led to unnecessary studies in children. It is acknowledged that

some learning process had to take place but this situation is repeating itself, including with

experienced companies.

The Agency will therefore monitor closely the compliance with this requirement of the Regulation and

will present the outcome in the next report.

3.2. Validation of application for marketing authorisation/extension

As set out in Article 7 of the Paediatric Regulation, applications concerning a medicinal product not

authorised in the EEA on 26 July 2008, must include one of the following in order to be considered

‘valid’:

• The results of all studies performed and details of all information collected in compliance with an

agreed Paediatric Investigation Plan (PIP).

This means that the application will have to include the PIP decision but also the results in accordance

with the agreed PIP.

• A decision of the EMEA on a PIP including the granting of a deferral.

This means that the application will have to include the PIP decision including the deferral granted.

• A decision of the EMEA granting a product-specific waiver.

• A decision of the EMEA granting a class waiver on condition.

The same requirements as set out in Article 8 of the Paediatric Regulation, apply to applications

submitted from 26 January 2009, for new indication(s), new pharmaceutical form(s) and/or new

route(s) of administration concerning an authorised medicinal product protected either by a

supplementary protection certificate or by a patent which qualifies for the granting of such a

certificate:

• So far it seems that no application falling under Article 7 or 8 has been validated without having

complied with these requirements at the Agency level.


• For the centralised procedure, despite early identification of applicants, and reminders (letters were

sent to future applicants in 2007) a few companies have submitted their application for marketing

authorisation or application to add a new indication, new pharmaceutical form, new route of

administration without having either a Decision on a PIP or on a waiver, or without having

requested prior to the submission an opinion on the compliance check from the PDCO. This has

resulted in a couple of delays for the start of the procedure.

3.3. Compliance with the paediatric requirements and rewards

So far there is no indication that a company has benefited from the reward without having complied

with the paediatric requirements set in the Regulation.

3.4. Mention of the Decision on waivers or deferrals in the product information

There is a requirement set in the Regulation (Article 28(2)) to include in the marketing authorisation

granted or varied a statement on the waiver or deferral. However, the Guideline on the Summary of

Product Characteristics was only revised in September 2009 and applies as of 1st May 2010. The

guideline provides guidance on how to word statements on waivers and deferrals. Obviously,

submissions may also be made on the basis of this guidance, prior to the implementation date.

For the centralised procedure, only a few products were identified for which this statement has been

omitted. It is planned to correct the situation at the next regulatory procedure involving an

amendment of the Summary of Product Characteristics and a Procedural announcement was made

through the October 2009 CHMP meeting report.

Based on the information received from the Member States, it appears that no marketing authorisation

has been granted or varied for medicinal products for which an Agency decision on a waiver or deferral

has been issued to date.

3.5. Annual reports on deferrals

Article 34.4 of the Paediatric Regulation states that “in the case of a deferral, the marketing

authorisation holder shall submit an annual report to the Agency providing an update on progress with

paediatric studies in accordance with the decision of the Agency agreeing the paediatric investigation

plan and granting a deferral”.

The Agency had published guidance and a form for the electronic submission of the reports, and has

already received 13 reports. The Agency will analyse the adherence with such requirements and will

aim to report on this in the next report.

4. CONCLUSION

After three years of entry into force of the Paediatric Regulation, companies have already benefited

from incentives and rewards, and although still few, some companies have benefited from an extension

of the Supplementary Protection Certificate in some Member States. So far no companies have

benefited from 2-year extension of market exclusivity for an orphan medicinal product, nor from the

data and marketing protection periods granted for PUMA.

To date the Agency has not received any report identifying any failure to comply with any of the

obligations set in the Paediatric Regulation. However not all Member States have provided information

on this point. It has to be noted that the Commission Regulation on financial penalties has not been


revised as requested in Article 49(3) to make possible financial penalties linked to infringement of the

Paediatric Regulation.

In a wider context, it is already clear that the Regulation has created real awareness of the need for

conducting appropriate paediatric clinical trials and for developing suitable formulations for use in

children. It has become the norm to include the development of a medicinal product in children within

the development in adults, where relevant.

The Regulation is stimulating the conduct of high-quality ethical research, in particular through the

European network, and is promoting information with the transparency of agreed PIPs and waivers,

and the access to clinical trial data generated by research.


Annex 1 - Questions sent to the Member States

In addition to the Community rewards/incentives, and in accordance to Article 39 of Paediatric

Regulation, Member States may have introduced other measures that companies may benefit from

when developing medicinal products for paediatric use. The below list encompasses measures taken by

various Member States on the basis of the report published by the European Commission on 30 July

2008. For all the below items, if applicable to your Member State, please list the companies and

products that have benefited in 2007, 2008 and 2009, separated by year from:

1) Benefits

• Compliance statement included in a marketing authorisation for those products

approved nationally (number of statements, name of products and of marketing authorisation

holders).

• 6 months extension of the Supplementary of Protection Certificate granted by your National

Patent Office (number of extensions, name of products and patent holders).

This applies to products who have complied with Article 36 of the Paediatric Regulation.

• Price/reimbursement benefits (name of products marketing authorisation holders, type and

amount of concessions).

Your Member State may have introduced concessions granted for medicinal products for paediatric use

in connection with the fixing of prices and reimbursement, including priority review for this process.

• Grants for development (name of products, beneficiaries and type of support).

Your Member State may have provisions for funding support to the development of medicinal products

for paediatric use.

• Clinical trials, Marketing Authorisation.

Your Member State may have introduced fee reduction/fee waiver for:

• Authorisation of paediatric clinical trials (name of products, sponsors, type and amount of fee

reduction/waiver).

• Request for national scientific advice to help companies wishing to develop medicinal products for

paediatric use (number of advice, name of products and of marketing authorisation holders).

• Granting of and/or extension of the marketing authorisation, including for Paediatric Use Marketing

Authorisation (PUMA) (type and amount of fee reductions, name of products and marketing

authorisation applicant/holder).

• Your Member State may have introduced policy for priority review of the applications for marketing

authorisation for products for paediatric use (number of priority reviews, PUMA, name of products

and marketing authorisation holder).

• Paediatric Use Marketing Authorisation (PUMA) granted nationally* (number, name of products and

marketing authorisation holder).

• National marketing Authorisation/extension granted with statement on deferral/waiver in the

product information (number, products, marketing authorisation holder).


2) Infringement

• Application for marketing authorisation/extension submitted and validated without compliance with

Article 7 or 8 of the Paediatric Regulation (number, product, date of marketing authorisation,


• Reward obtained without inclusion on the product information of the paediatric data (products,


• Marketing authorisation granted or varied without any mention of the waiver or deferral in the

Summary of Product Characteristics (products, marketing authorisation holder).

* For those products submitted under mutual recognition or decentralised products the European Medicines Agency will contact the Coordination Group (CMD(h)) directly.


Annex 2 - Compliance statement included in a marketing authorisation for products authorised through national/decentralised/mutual recognition procedure

Austria

• Cosaar 12,5 mg Filmtabletten, NL/H/1457/001, MAH = Merck Sharp & Dohme

GmbH: 1 compliance statement (04.05.2009)

• Cosaar 50 mg Filmtabletten, NL/H/1457/002, MAH = Merck Sharp & Dohme


• Cosaar 100 mg Filmtabletten, NL/H/1457/003, MAH = Merck Sharp & Dohme


• Cosaar 2,5 mg Pulver und Lösungsmittel zur Herstellung einer Suspension, NL/H/1457/004, MAH =

Merck Sharp & Dohme GmbH: 1 compliance statement (13.11.2009)

• Arimidex 1 mg Filmtabletten, UK/H/0111/001, MAH = AstraZeneca Österreich

GmbH: national implementation is ongoing

(Variation to introduce data an paediatric use in accordance with the European Commission

Decision issued in Nov. 2009 was approved on 18.12.2009)

There were no compliance statements introduced in marketing authorisation in 2007 or 2008.

Belgium

No information provided (although information has been provided on the 6-month extension of the

Supplementary Protection Certificated).

Bulgaria

Arimidex 1 mg film-coated tablet, anastrozole, AstraZeneca Pharmaceuticals AB.

Czech Republic

None.

Cyprus

None.

Denmark

• Cozaar (losartan potassium) Merck Sharp & Dohme BV, The Netherlands.

• Arimidex (anastrozol) from AstraZeneca A/S, Denmark.


Estonia

• Cozaar (losartan potassium) Merck Sharp & Dohme.


• Arimidex (anastrozol) from AstraZeneca UK Ltd.


Finland

• Arimidex 1 mg tabletti (MAnr12097 Hnr1 193367/2009) AstraZeneca Oy (Type II variation

application approved 16.12.2009).

• Cozaar 12,5 mg tabletti kalvopäällysteinen (MAnr 12916 Hnr 172362/2008

NL/H/1457/01/II/02) Merck Sharp & Dohme B.V (type II variation approved 8-05-2009) PIP

compliance statement.

• Cozaar 50 mg tabletti kalvopäällysteinen (MAnr 11637 Hnr 172363/2008

NL/H/1457/01/II/02) Merck Sharp & Dohme B.V (type II variation approved 8-05-2009) PIP


• Cozaar 100 mg tabletti kalvopäällysteinen (MAnr 16602 Hnr 172364/2008 NL/H/1457/01/II/02

Merck Sharp & Dohme B.V - (type II variation approved 8-05-2009) PIP compliance statement.

• Cozaar 2,5 mg/ml jauhe ja liuotin oraalisuspensiota varten (MAnr 25172 Hnr 161675/2009),

Merck Sharp & Dohme B.V – (line extension approved 26-02-2009).

• Cozaar 2,5 mg/ml jauhe ja liuotin oraalisuspensiota varten (MAnr 25172 Hnr 180745/2009

NL/H/1457/01/II/02), Merck Sharp & Dohme B.V – (type II variation approved 23-09-2009) PIP


France

No information provided (although information has been provided on the 6-month extension of the

Supplementary Protection Certificated)

Germany

• Arimidex (anastrozol) from AstraZeneca.

• Cosaar (losartan).


Hungary

There were no compliance statements introduced in marketing authorisation in 2007, 2008 or 2009.

Ireland

• Cozaar (losartan) 2.5mg powder and solvent for oral solution (PA 0970/003/001): Marketing

Authorisation Holder: Merck Sharp and Dohme.

• Arimidex 1mg film coated tablets (PA 1286/004/004): Marketing Authorisation Holder: Astra

Zeneca UK Limited.



Italy

• Lortaan (losartan potassium) (MSD) NL/H/1457/01-04.

• Neo-Lotan (losartan potassium) NL/H/1457/01-04.

• Losaprex (losartan potassium) NL/H/1457/01-04.

• Arimidex (AstraZeneca) UK/H/111/01.

Latvia


Lithuania


Luxembourg


The Netherlands

There were 2 products for which a compliance statement has been introduced in the marketing

authorisation.

Malta


Romania

2009: COZAAR 2,5 mg/ml powder and solvent for oral suspension Merck Sharpe & Dohme Romania

SRL.

Slovakia


Slovenia

• Arimidex 1 mg film-coated tablet, anastrozole, AstraZeneca UK Limited.

• Cozaar 12,5 mg film-coated tablets, Merck Sharp & Dohme inovativna zdravila d.o.o - Cozaar 50

mg film-coated tablets, Merck Sharp & Dohme inovativna zdravila d.o.o - Cozaar 100 mg film-

coated tablets, Merck Sharp & Dohme inovativna zdravila d.o.o.

• Cozaar 2,5 mg/ml powder and vehicle for oral suspension, Merck Sharp & Dohme inovativna

zdravila d.o.o.

Sweden

• Cozaar film coated tablet and powder and solvent for oral suspension, MAH is Merck Sharp &

Dohme BV, The Netherlands and the representative is Merck Sharp & Dohme AB, Sweden.


• Arimidex film coated tablet, MAH is AstraZeneca AB, Södertälje, Sweden.

United Kingdom

• Cozaar (Merck, Sharp and Dohme Ltd) compliance statement included in UK MA on 6/5/2009.

• Arimidex (Astra Zeneca) compliance statement included in UK MA on 18/12/2009.



Annex 3 - 6-months extension of the supplementary protection certificate (SPC) granted by the National Patent Office

Austria

No information provided.

Belgium

• Coozar (losartan potassium) Merck Sharp & Dohme Inc.

• Request for Caspofungine under evaluation Merck Sharp & Dohme.

Bulgaria

There are no SPCs granted during 2009.

Czech Republic

No extension has been granted yet.

Cyprus

No extension has been granted yet.

Denmark

In 2009 granted 2 extensions of the Supplementary Protection Certificate for losartan potassium

(Cozaar), patent holder E.I. du Pont de Nemours and Company and Caspofunginacetat (Cancidas)

patent holder Merck & Co.

Udstedte forlængelser af supplerende beskyttelsescertifikat (Issued extensions of SPCs):

Indl.dag: 2009-02-24

Certifikat ans.nr: CA 2004 00003

Udløbsdag (expire): 2010-03-02

Grundpatent nr (Patent no): PR 174700

Ansøger (Applicant): E.I. DU PONT DE NEMOURS AND COMPANY, 1007 Market Street, Wilmington,

Delaware 19898, USA

Fuldmægtig: Zacco Denmark A/S, Hans Bekkevolds Allé 7, 2900 Hellerup, Danmark

DK markedsførelsestilladelse nr (MA no): MT 15844

Dato for samme: 1994-09-26

Produkt (product): Losartankalium

Første markedsføringstilladelse i EU (First MA in EU): 12209

Dato for samme (Date for first MA in EU): 1994-09-02

Benævnelse: Substituerede imidazoler samt farmaceutisk præparat

indeholdende dem

Indl.dag: 2002-04-19

Certifikat ans.nr: CA 2002 00007

Udløbsdag: 2017-04-24

Grundpatent nr: DK/EP 0620232


Ansøger: Merck & Co., Inc., 126, East Lincoln Avenue, P.O. Box 2000, Rahway, New Jersey 07065-

0900, USA

Fuldmægtig: Zacco Denmark A/S, Hans Bekkevolds Allé 7, 2900 Hellerup, Danmark

DK markedsførelsestilladelse nr: EU/1/01/196/001-003


Produkt: Caspofunginacetat

Første markedsføringstilladelse i EU: EU/1/01/196/001-003


Benævnelse: Azacyclohexapeptid-forbindelser

Estonia


France

• Cozaar: laboratoires Merck-Sharp & Dohme-Chibret.

• Arimidex: laboratoires AstraZeneca.

Finland

No information provided apart from the link to the National Board of Patents and Registration of

Finland (NBPR) website http://www/prh.fi/en.html.

Germany

Certificate (Schutzzertifikat DE 196 75 001)

Handelsnamen (z.B) Cosaar, Cozaar oder Lorzaar

Wirkstoffname/Bezeichnung des Erzeugnisses: Losartan-Kalium

Schutzzertifikatsinhaber: EI. Du Pont de Nemours & Co

Certificate (Schutzzertifikat DE 102 99 013)

Handelsnamen (z.B) Cancidas

Wirkstoffname/Bezeichnung des Erzeugnisses: Caspofungin

Schutzzertifikatsinhaber: Merck & Co

Hungary


Ireland

2009: Merck Sharpe and Dohme Cozaar.

Italy

• Lortaan (MSD) NL/H/1457/04/II/04 N. 754 20/10/09


• Neo-Lotan NL/H/1457/04/II/04 “N. 753 20/10/09

• Losaprex NL/H/1457/04/II/04.” N. 755 20/10/09

• Arimidex (AstraZeneca) UK/H/111/01/II/52 Provv 946 del 18/12/09

Latvia


Lithuania

No SPC has been granted.

Luxembourg


Malta


The Netherlands


Romania


Slovak Republic


Slovenia


Sweden

No information.

United Kingdom

2009

• Caspofungin (Merck & Co, Inc) SPC extension granted 30 July 2009

SPC/GB/02/002 extended until 23 April 2017

• losartan (EI du Pont Nemours & Co) SPC extension granted 24 August 2009

SPC/GB/95/010 extended until 1 March 2010


Annex 4 – List of projects on off-patent medicines funded by the European Commission through the EU Framework Programme

2008

• LOULLA & PHILLA

Development of oral liquid formulations of Methotrexate and 6-Mercaptopurine for paediatric acute

lymphoblastic leukaemia (ALL).

• TINN

Aims to evaluate PK & PD of ciprofloxacin and fluconazole in neonates.

• O3K

Oral liquid formulations of Cyclophosphamide and Temozolomide.

• NEUROSIS

Efficacy of Budesonide (BS) in reducing bronchopulmonary dysplasia (BPD).

• EPOC

Aims to evaluate pharmacokinetics and pharmacodynamics of doxorubicin.

• NeoOpioid

Compares morphine and fentanyl in pain relief in pre-term infants.

2009

• NEMO

Evaluates the efficacy safety, PK, PD, mechanisms of action of bumetanide in neonatal seizures,

including the effect on neurodevelopment and to develop and adapt a bumetanide formulation

suitable for newborns in order to apply for a Paediatric Use Marketing Authorisation (PUMA).

• NeoMero

European multicentre network to evaluate pharmacokinetics, safety and efficacy of Meropenem in

neonatal sepsis and meningitis.

• PERS

Focuses on two indications, the use of risperidone in children and adolescents with conduct

disorder who are not mentally retarded, and the use of risperidone in adolescents with

schizophrenia.


Annex 5 - List of products and resulting amendment of the SmPC further to submission of data through article 45 and 46

Article 45

Centrally authorised medicinal products

International

Non-

proprietary

name

Invented

name

Marketing

authorisation

holders

Change in the

Summary of

Product

Characteristics

Link to EPAR

Pegfilgrastim Neulasta Amgen

Europe B.V.

Section 4.2 and

introduction of new

information in

sections 4.8, 5.1

and 5.2

http://www.ema.europa.eu/human

docs/PDFs/EPAR/neulasta/296102e

n8b.pdf

Ritonavir Norvir Abbott

Laboratories

Limited

Section 5.1 http://www.ema.europa.eu/human

docs/PDFs/EPAR/Norvir/H-127-

en8b.pdf

Mangafodipir Teslascan GE

Healthcare

AS

Section 4.2

http://www.ema.europa.eu/human

docs/PDFs/EPAR/Teslascan/013097

en8b.pdf

Interferon

beta-1a

Avonex Biogen Idec

Limited

Sections 4.2, 4.8

and 5.1

CHMP opinion 2010

Medicinal products authorised through national/mutual recognition/decentralised procedure

Tranexamic

Acid

Exacyl,

Ugurol

Sanofi-

Aventis,

Rottapharm

Section 4.2 and

5.1 (+ other

sections not

specifically linked

to submission of

paediatric data)

http://www.hma.eu/fileadmin/datei

en/Human_Medicines/CMD_h_/Pae

diatric_Regulation/Assessment_Rep

orts/Article_45_work-

sharing/Tranexamic_acid_45PaedA

R.pdf

Amlodipine Pfizer Section 4.2 (dose

recommendation),

5.1 and 5.2





sharing/Amlodipine_2009_11_45Pd

AR.pdf

Bisacodyl Dulcolax

Prepacol

Fenolax

Boehringer

Ingelheim

Guerbet

ICN Polfa

Rzeszow

Harmonisation of

section 4.2





sharing/Bisacodyl_2009_12_45PdA

R.pdf

Felodipine

Renedil,

Prevex,

Plendil

Sanofi-

Aventis

Section 5.1 and

5.2







sharing/Felodipine_2009_11_45PdA

R.pdf

Glucosamine

Donacom

and other

trade

names

Rottapharm

Ltd

Harmonisation of

section 4.2 and 4.4





sharing/Glucosamine_2009_11_45P

dAR.pdf

Lisinopril Prinivil,

Zestril

Merck, Astra

Zeneca

4.2 (dose

recommendations)

4.8, 5.1 and 5.2





sharing/Lisinopril_2009_11_45PdA

R.pdf

Adumbran Oxazepam Boehringer

Ingelheim

Section 4.4 http://www.hma.eu/fileadmin/datei




sharing/Oxazepam_2009_09_Paed

AR.pdf

Salmon

Calcitonin

Calsynar

Calcitonin

armour

Tonocalcin

Aventis

Pharma

Rorer

Pharma-

ceuticals

Alfa Biotech,

Alfa

Wasserman

Section 4.2 http://www.hma.eu/fileadmin/datei




sharing/Salmon_calcitonin_45Paed

PAR.pdf

Simvastatin Zocor Merck

Sharpe &

Dohme

GmbH

4.2 (dose

recommendations)

4.3, 4.4, 4.8, 5.1

and 5.2





sharing/simvastatin_45PaedPAR_.p

df


Article 46


International

Non-

proprietary

name

Invented

name

Marketing

authorisation

holders

Change in the

Summary of

Product

Characteristics

Link to EPAR

Cinacalcet Mimpara Amgen Europe

B.V

Section 5.2 http://www.ema.europa.eu/humando

cs/PDFs/EPAR/mimpara/H-570-

en8.pdf

Telithromycin Ketek Aventis Pharma

S.A.

Section 4.2

and 5.2

http://www.ema.europa.eu/humando

cs/PDFs/EPAR/ketek/H-354-en8.pdf

Documents

Report to the European Commission